Mesh pouches for implantable medical devices

ABSTRACT

Biodegradable polymer-coated surgical meshes formed into pouches are described for use with cardiac rhythm management devices (CRMs) and other implantable medical devices. Such meshes are formed into a receptacle, e.g., a pouch or other covering, capable of encasing, surrounding and/or holding the cardiac rhythm management device or other implantable medical device for the purpose of securing it in position, inhibiting or reducing bacterial growth, providing pain relief and/or inhibiting scarring or fibrosis on or around the CRM or other implantable medical device. Preferred embodiments include surgical mesh pouches coated with one or more biodegradable polymers that can act as a stiffening agent by coating the filaments or fibers of the mesh to temporarily immobilize the contact points of those filaments or fibers and/or by increasing the stiffness of the mesh by at least 1.1 times its original stiffness. The pouches of the invention can also provide relief from various post-operative complications associated with their implantation, insertion or surgical use, and, optionally, include one or more drugs in the polymer matrix of the coating to provide prophylactic effects and/or alleviate side effects or complications associated with the surgery or implantation of the CRM or other implantable medical device.

This application is a continuation-in-part of U.S. Ser. No. 11/672,929,filed Feb. 8, 2007, which claims priority under 35 U.S.C. §119(e)(5) ofU.S. Provisional Patent Application No. 60/864,597, filed Nov. 6, 2006and U.S. Provisional Patent Application No. 60/771,827, filed Feb. 8,2006; this application also claims priority under 35 U.S.C. §119(e)(5)to U.S. Provisional Patent Application No. 60/984,254, filed Oct. 31,2007 and to U.S. Provisional Patent Application No. 60/864,597, filedNov. 6, 2006, each of which are incorporated herein by reference.

FIELD OF THE INVENTION

Biodegradable polymer-coated surgical meshes formed into pouches aredescribed for use with cardiac rhythm management devices (CRMs) andother implantable medical devices IMDs). Such meshes are formed into areceptacle, e.g., a pouch or other covering, capable of encasing,surrounding and/or holding the CRM or other IMD for the purpose ofsecuring it in position, inhibiting or reducing bacterial growth,providing pain relief and/or inhibiting scarring or fibrosis on oraround the CRM or other IMD. Preferred embodiments include surgical meshpouches coated with one or more biodegradable polymers that can act as astiffening agent by coating the filaments or fibers of the mesh totemporarily immobilize the contact points of those filaments or fibersand/or by increasing the stiffness of the mesh by at least 1.1 times itsoriginal stiffness. The pouches of the invention can also provide relieffrom various post-operative complications associated with theirimplantation, insertion or surgical use, and, optionally, include one ormore drugs in the polymer matrix of the coating to provide prophylacticeffects and/or alleviate side effects or complications associated withthe surgery or implantation of the CRM or other IMD.

BACKGROUND OF THE INVENTION

Prosthetic implants such as meshes, combination mesh products or otherporous prostheses are commonly used to provide a physical barrierbetween types of tissue or extra strength to a physical defect in softtissue. However, such devices are often associated with post-surgicalcomplications including post-implant infection, pain, excessive scartissue formation and shrinkage of the prosthesis or mesh. Excessive scartissue formation, limited patient mobility, and chronic pain are oftenattributed to the size, shape, and mass of the implant and a variety ofefforts have been undertaken to reduce the amount of scar tissueformation. For example, lighter meshes using smaller fibers, largerweaves, and/or larger pore sizes as well as meshes woven from bothnon-resorbable and resorbable materials are in use to address theseconcerns.

For treating acute pain and infection, patients with implantedprostheses are typically treated post-operatively with systemicantibiotics and pain medications. Patients will occasionally be givensystemic antibiotics prophylactically; however, literature review ofclinical trials does not indicate that systemic antibiotics areeffective at preventing implant-related infections.

In 1992, it was reported that nosocomial infections involved over 2million patients each year and cost the healthcare systems over 4.5billion dollars annually.¹ Today, these numbers are undoubtedly muchhigher. Surgical site infections, involving approximately 500,000patients, represent the second most common cause of nosocomialinfections and approximately 17% of all hospital-acquired infections.²The incidence of infections associated with the placement of pacemakershas been reported as 0.13 to 19.9% at an average cost of $35,000 totreat these complications which most often involves complete removal ofthe implant.^(3,4)

Post-operative infection is tied to three elements: lack of host defensemechanisms, surgical site and bacteria present at the time of deviceimplantation.⁵ The general health of the patient (i.e., the host factor)is always important; however, since many patients requiring surgery arecompromised in some way—and there is little that can be done to mitigatethat factor—controlling the other two factors becomes important.

Studies have shown that patients are exposed to bacterial contaminationin the hospital, especially in the operating room (OR) and along theroute to the OR⁶ In fact, bacterial counts of up to 7.0×10⁴ CFU/m² havebeen found in the OR dressing area.⁶ Recent improvements in air handlingand surface cleansing have reduced the environmental levels ofinfectious agents, but not eliminated them. Consequently, further meansto reduce bacterial contamination or to reduce the potential forbacterial infection are desirable.

Controlling the inoculation levels is the third component to the intra-and post-operative surgical infection control triad. One aspect tomicrobial control is the use antibiotics. For example, one practiceadvocates the administration of systemic antibiotics within 60 minutesprior to incision, with additional dosing if the surgery exceeds 3hours.⁵ Such pre-incision administration has shown some positive effectson the incidence of infection associated with the placement ofpacemakers.⁷ An adjunctive approach to managing the potential forimplant contamination has been the introduction of antimicrobial agentson implantable medical devices.^(8,9)

This approach was initially developed to create a barrier to microbialentry into the body via surface-penetrating devices, such as indwellingcatheters,⁹⁻¹¹ The antimicrobial agents were applied in solution as adirect coating on the device to prevent or reduce bacterial colonizationof the device and, therefore, reduce the potential for a device-relatedinfection. While a number of clinical trials have demonstrated thatantimicrobial coating on devices, such as central venous cathetersreduce device colonization, reduction of infection has not beenstatistically significant although the numerical trends show a reductionin patient infection.¹²⁻¹⁸ These results are highly relevant since theytend to establish that, with proper aseptic and surgical techniques aswell as administration of appropriate antibiotic therapy, the use ofsurface-modified devices has a positive impact on the overallprocedural/patient outcome.^(12,13)

The development of post-operative infection is dependent on manyfactors, and it is not clear exactly how many colony forming units(CFUs) are required to produce clinical infection. It has been reportedthat an inoculation of 10³ bacteria at the surgical site produces awound infection rate of 20%.⁵ And while current air-handling technologyand infection-control procedures have undoubtedly reduced the microbiallevels in the hospital setting, microbial contamination of animplantable device is still possible. It is known that bacteria, such asStaphylococcus can produce bacteremia within a short time afterimplantation (i.e., within 90 days) with a device or lay dormant formonths before producing an active infection so eradication of thebacterial inoculum at the time of implantation is key and may help toreduce late-stage as well as early-stage device-related infections.²²

For example, the combination of rifampin and minocycline hasdemonstrated antimicrobial effectiveness as a coating for catheters andother implanted devices, including use of those drugs in anon-resorbable coating such as silicone and polyurethane.^(13, 19-21)The combination of rifampin and minocycline has also been shown toreduce the incidence of clinical infection when used as a prophylacticcoating on penile implants.

The parent case of this application (U.S. Ser. No. 11/672,929) describesa bioresorbable polymer coating on a surgical mesh as a carrier for theantimicrobial agents rifampin and minocycline. Such meshes can befashioned into a pouch of various sizes and shapes to match theimplanted pacemakers, pulse generators, defibrillators and otherimplantable medical devices. The addition of the antimicrobial agentspermits the pouch to deliver antimicrobial agents at the implant siteand thus to provide a barrier to microbial colonization of a CRM duringsurgical implantation as an adjunct to surgical and systemic infectioncontrol.

The present invention addresses these needs (preventing or inhibitinginfections) as well as others, such as pain relief and inhibition orreduction of scar tissue, fibrosis and the like, by providingtemporarily stiffened meshes formed into pouches or other receptacles tohold an implantable medical device upon implantation.

SUMMARY OF THE INVENTION

The present invention relates to pouches, coverings and the like madefrom implantable surgical meshes comprising one or more biodegradablepolymer coatings. The mesh pouches of the invention can be shaped asdesired into pouches, bags, coverings, shells, skins, receptacles andthe like to fit any implantable medical device. Preferred meshes of theinvention are comprised of woven polypropylene coated with one or morebiodegradable polymer to impart drug elution or other temporary effects.

As used herein, “pouch,” “pouches,” “mesh pouch,” “mesh pouches,” “pouchof the invention” and “pouches of the invention” means any pouch, bag,skin, shell, covering, or other receptacle made from an implantablesurgical mesh comprising one or more biodegradable polymer coatings andshaped to encapsulate, encase, surround, cover or hold, in whole or insubstantial part, an implantable medical device. The pouches of theinvention have openings to permit leads and tubes of the IMD to extendunhindered from the IMD though the opening of the pouch. The pouches mayalso have porosity to accommodate monopolar devices that require the IMDto be electrically grounded to the surrounding tissue. An IMD issubstantially encapsulated, encased, surrounded or covered when thepouch can hold the device and at least 20%, 30%, 50%, 60%, 75%, 85%,90%, 95% or 98% of the device is within the pouch or covered by thepouch.

In accordance with this invention, the coated surgical meshes can beformed to encapsulate a pacemaker, a defibrillator, a generator, animplantable access system, a neurostimulator, or any other implantabledevice for the purpose of securing them in position, providing painrelief, inhibiting scarring or fibrosis and/or inhibiting bacterialgrowth. Such coated meshes are formed into an appropriate shape eitherbefore or after coating with the biodegradable polymers.

In one aspect, the pouches of the invention may act as medicalprostheses (providing support to the device and the tissue surroundingthe area of implant), and are thus also referred to as medicalprostheses.

Hence, the pouches of the invention comprise a mesh and one or morecoating which temporarily stiffens the mesh to at least 1.1 times itsoriginal stiffness. The coatings on such meshes do not alter theintegrity of the mesh and thus allow the mesh to remain porous. Ingeneral, the coatings do not substantially alter the porosity of themesh. More particularly, the pouches of the invention comprise a meshwith one or more coatings with at least one of the coatings comprising astiffening agent(s) that coats the filaments or fibers of the mesh so totemporarily immobilize the contact points of those filaments or fibers.Again, the coatings on such meshes do not alter the integrity orstrength of the underlying mesh and allow the mesh to remain porousafter coating. In general, the coatings do not substantially alter theporosity of the mesh. The meshes are capable of substantially revertingto their original stiffness under conditions of use.

The stiffening agents, i.e., as applied in the coatings of theinvention, can selectively, partially or fully coat the contact pointsof the filaments or said fibers of the mesh to create a coating. Thecontact points generally include the knots of woven meshes. Such coatingare can be positioned on the mesh in a templated pattern or in an arraysuch as might be deposited with ink-jet type technology, includingcomputer controlled deposition techniques. Additionally, the coatingscan be applied on one or both sides of the mesh.

In some embodiments, the stiffening agents include hydrogels, eitheralone or in combination with one or more biodegradable polymers. In someembodiments, the stiffening agent is one or more biodegradable polymers,and can be applied in layers. One or more biodegradable polymers can beused per individual coating layer. Preferred biodegradable polymercomprises one or more tyrosine-derived diphenol monomer units aspolyarylates, polycarbonates or polyiminocarbonates.

In another aspect of the invention, the pouches of the invention have atleast one of the coatings that further comprises one or more drugs. Suchdrugs include, but are not limited to, antimicrobial agents,anesthetics, analgesics, anti-inflammatory agents, anti-scarring agents,anti-fibrotic agents, leukotriene inhibitors as well as other classes ofdrugs, including biological agents such as proteins, growth inhibitorsand the like.

The biodegradable polymer coatings are capable of releasing one or moredrugs into surrounding bodily tissue and proximal to the device suchthat the drug reduces or prevents implant- or surgery-relatedcomplications. For example, by including an anesthetic agent in thecoating that predictably seeps or elutes into the surrounding bodilytissue, bodily fluid, or systemic fluid, one has a useful way toattenuate pain experienced at the implantation site. In another example,replacing the anesthetic agent with an anti-inflammatory agent providesa way to reduce the swelling and inflammation associated implantation ofthe mesh, device and/or pouch. In yet another example, by delivering anantimicrobial agent in the same manner, one has a way to provide a rateof drug release sufficient to prevent colonization of the mesh pouch,the CRM or other IMD and/or the surgical implantation site by bacteriafor at least the period following surgery necessary for initial healingof the surgical incision.

The coatings on the pouches of the invention can deliver multiple drugsfrom one or more independent layers, some of which may contain no drug.

The invention thus provides a method of delivering drugs at controlledrates and for set durations of time using biodegradable, resorbablepolymers from a coating on a surgical mesh formed as a pouch of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. graphically depicts the zone of inhibition (ZOI) forpolyarylate-coated meshes containing rifampin and minocyclinehydrochloride that have been incubated on Staphylococcus aureus lawnsfor the indicated times (Example 1). The symbols represent the followingmeshes: ♦, P22-25 20 passes; ▪, P22-25 40 passes; ▴, P22-25 80 passes;x, P22-27.5 20 passes; *, P22-27.5 40 passes; ●, P22-27.5 80 passes; and|, catheter.

FIG. 2 graphically depicts cumulative bupivacaine release frommultilayer polyarylate-coated meshes in PBS.

FIG. 3 graphically depicts cumulative bupivacaine release frommultilayer polyarylate-coated meshes having various loadings ofbupivacaine. The symbols represent the following meshes: ♦, P22-27.5 (11passes, 1 dip); ▪, P22-27.5 (11 passes, 2 dips); and ▴, P22-27.5 (2passes, 2 dips).

FIG. 4 graphically depicts the time course of dermal anesthesia from 1×2cm surgically implanted, polyarylate meshes containing 7.5 mg/cm²bupivacaine. Meshes were implanted in rats by subcostal laparotomy,pin-prick responses were determined and are shown as % pain responseinhibition (see Examples for details). The “*” indicates statisticallysignificant response at p<0.05 compared to the baseline pin-prickresponse.

FIG. 5 graphically depicts mesh stiffness. The bars, from top to bottom,represent the stiffness for (1) a PPM3 mesh without a polyarylatecoating and without sterilization, (2) a Prolene™ (Ethicon) meshsterilized with ethylene oxide, (3) a polyarylate-coated PPM3 mesh 12months after coating and sterilized by gamma irradiation with a nitrogenflush, and (4) a polyarylate-coated PPM3 mesh 12 months after coatingand sterilized by gamma irradiation.

FIG. 6 graphically depicts the change in mesh stiffness over time duringthe course of polymer degradation for a polymer-coated PPM3polypropylene mesh soaking in PBS at 37° C.

FIG. 7 depicts micrographs of a tyrosine polyarylate-coated mesh. Thetop left panel shows the woven nature of the mesh and the contact pointsof the filaments. The bottom left panel demonstrates the coating overthe contact points of the mesh filaments. The right panel is a scanningelectron micrograph of a coated filament.

FIG. 8 provides an optical image of a mesh having a tyrosine polyarylatecoating containing rifampin and minocycline. On the left, the opticalimage; on the right, a schematic thereof indicating the areas of intenseorange color by the circled areas filled with diagonal lines.

FIG. 9 shows a schematic diagram of a polymer-coated CRM pouch with theCRM inserted in the pouch.

FIG. 10 is a picture of a polymer-coated pouch containing a CRM.

FIG. 11 is a micrograph showing the implant site of a coated-mesh pouchwith device at 14 weeks post-implantation (4× magnification).

DETAILED DESCRIPTION OF THE INVENTION

The pouches of the invention are formed from the coated implantablesurgical meshes and comprise a surgical mesh and one or morebiodegradable polymer coating layers with each coating layer optionally,and independently, further containing a drug. The physical, mechanical,chemical, and resorption characteristics of the coating enhance theclinical performance of the mesh and the surgeon's ability to implantthe device. These characteristics are accomplished by choosing asuitable coating thickness and the biodegradable polymer.

Mesh

A mesh in accordance with the invention is any web or fabric with aconstruction of knitted, braided, woven or non-woven filaments or fibersthat are interlocked in such a way to create a fabric or a fabric-likematerial. As used in accordance with the present invention, “mesh” alsoincludes any porous prosthesis suitable for temporarily stiffening.

Surgical meshes are well known in the art and any such mesh can becoated as described herein. The meshes used in the present invention aremade from biocompatible materials, synthetic or natural, including butnot limited to, polypropylene, polyester, polytetrafluoroethylene,polyamides and combinations thereof. One of the advantages of thepresent invention is that the coatings can be used with any commerciallyavailable mesh. A preferred mesh is made from woven polypropylene. Poresizes of meshes vary. For example the Bard Marlex® mesh has pores of379+/−143 micrometers or approx. 0.4 mm, whereas the Johnson and JohnsonVypro® mesh has pores of 3058+/−62 micrometers or approx. 3 mm.

The stiffening agents of the invention include hydrogels, biodegradablepolymers and any other compound capable of imparting temporary stiffnessto the mesh in accordance with the invention. Temporary stiffness meansthat, relative to the corresponding uncoated mesh material, there is anincrease in stiffness when one or more coatings are applied inaccordance with the invention. Upon use, those coatings then soften ordegrade over time in a manner that causes the mesh to revert back to itsoriginal stiffness, revert nearly back to its original stiffness orsufficient close to its original stiffness to provide the desiredsurgical outcome and the expected patient comfort. To determine if themedical prosthesis has temporary stiffness, the prosthesis can beevaluated in vitro or in vivo. For example, a coating can be applied tothe mesh and then the mesh left in a physiological solution for a periodof time before measuring its stiffness. The time period of stiffness iscontrolled by the degradation rate (for biodegradable polymers) orabsorption ability (for hydrogels). The time period can vary from days,to weeks or even a few months and is most conveniently determined invitro. Meshes with that revert to their original stiffness in vitrowithin a reasonable time (from 1 day to 3-4 months) are considered to betemporarily stiffened. Additionally, animal models can be used to assesstemporary stiffness by implanting the mesh and then removing it from theanimal and determining if its stiffness had changed. Such in vivoresults can be correlated with the in vitro results by those of skill inthe art. Methods to measure stiffness of a mesh or a coated mesh areknown in the art.

A hydrogel is composed of a network of water-soluble polymer chains.Hydrogels are applied as coatings and dried on the mesh. Upon use, e.g.,implantation in the body, the hydrogel absorbs water and become soft(hydrogels can contain over 99% water), thereby increasing theflexibility of the mesh and reverting to the original or near originalstiffness of the mesh. Typically, hydrogels possess a degree offlexibility very similar to natural tissue, due to their significantwater content. Common ingredients for hydrogels, include e.g. polyvinylalcohol, sodium polyacrylate, acrylate polymers and copolymers with anabundance of hydrophilic groups.

Meshes can have one or more polymer coatings and can optionally includedrugs in the coatings. Meshes with a single coating are useful toimprove handling of the mesh during surgical implantation and use.Meshes with drugs can be coated with single or multiple layers,depending on the amount of drug to be delivered, the type of drug anddesired release rate. Each layer can contain the same or differentpolymers, the same or different drugs, and the same or different amountsof polymers or drugs. For example, a first coating layer can containdrug, while the second layer coating layer contains either no drug or alower concentration of drug.

The biodegradable coating deposited onto the surface of the mesh givesthe mesh superior handling characteristics relative to uncoated meshesand facilitates surgical insertion because it imparts stiffness to themesh and thereby improves handling thereof. Over time, however, thecoating resorbs, or the stiffening agents degrades or softens, to leavea flexible mesh that provides greater patient comfort without loss ofstrength.

The surgical mesh can be coated with the biodegradable polymer usingstandard techniques such as spray or dip coating to achieve a uniformcoating having a thickness that provides at least 1.1 to 4.5 and morepreferably 1.25 to 2 times the stiffness of the uncoated mesh. Inaddition, the coating is optimized to provide for a uniform, flexible,non-flaking layer that remains adhered to the mesh throughout theimplantation and initial wound healing process. Typically, the polymercoating must maintain its integrity for at least 1 week. Optimal coatingsolutions are obtained by choosing a biodegradable polymer with asolubility between about 0.01 to about 30% in volatile solvents such asmethylene chloride or other chlorinated solvents, THF, various alcohols,or combinations thereof. Additionally, it is preferred to usebiodegradable polymers with a molecular weight between about 10,000 andabout 200,000 Daltons. Such polymers degrade at rates that maintainsufficient mechanical and physical integrity over about 1 week at 37° C.in an aqueous environment.

Additionally, a biodegradable polymer-coated implantable mesh isdescribed in which the biodegradable polymer layer (i.e., the coating)has a chemical composition that provide relatively good polymer-drugmiscibility. The polymer layer can contain between 1-80% drug at roomtemperature as well as between 1-95%, 2-80%, 2-50%, 5-40%, 5-30%, 5-25%and 10-20% drug or 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% drug as well as 5%increments from 10-95%, i.e., 10, 15, 20, 25, etc. In one embodiment,the biodegradable polymer coating releases drug for at least 2-3 days.Such release is preferred, for example, when the drug is an analgesic toaide in localized pain management at the surgical site. Such loading andrelease characteristics can be also be obtained for drugpolymer-combinations that do not have good miscibility by using multiplelayering techniques.

Additionally, the biodegradable polymer for use with the mesh pouch hasa chemical composition complementary to the drug so that the polymerlayer can contain between 2-50% drug at room temperature. For certaintypes of drug, the layer can contain as much as 80-90% drug and acts asdrug reservoir (or depot layer) and drug release can be controlled byusing multiple layers with varying amounts of drug (from none, to a fewpercent, saturation or above the solubility limit for the drug in thepolymer).

To achieve an analgesic affect, the anesthetic and/or analgesic shouldbe delivered to the injured tissue shortly after surgery or tissueinjury. A drug or drugs for inclusion in the coatings on the pouches ofthe invention include, but are not limited to analgesics,anti-inflammatory agents, anesthetics, antimicrobial agents, antifungalagents, NSAIDS, other biologics (including proteins and nucleic acids)and the like. Antimicrobial and antifungal agents can prevent the meshpouch, the device and/or the surrounding tissue from being colonized bybacteria. One or more drugs can be incorporated into the polymercoatings on the mesh pouches of the invention.

In another embodiment, a mesh pouch of the invention has a coatingcomprising an anesthetic such that the anesthetic elutes from theimplanted coated mesh to the surrounding tissue of the surgical site forbetween 1 and 10 days, which typically coincides with the period ofacute surgical site pain. In another embodiment, delivery of anantimicrobial drug via a mesh pouch of the invention can create aninhibition zone against bacterial growth and colonization surroundingthe implant during the healing process (e.g., usually about 30 days orless) and/or prevent undue fibrotic responses.

Using biodegradable polymer coatings avoids the issue of drugsolubility, impregnation or adherence in or to the underlying devicesince a coating having suitable chemical properties can be depositedonto the mesh, optionally in concert with one or more drugs, to providefor the release of relatively high concentrations of those drugs overextended periods of time. For example, by modulating the chemicalcomposition of the biodegradable polymer coating on the mesh pouch andthe coating methodology, a clinically-efficacious amount of anestheticdrug can be loaded onto a mesh pouch to assure sufficient drug elutionand to provide surgical site, post-operative pain relief for thepatient.

To provide such post-operative, acute pain relief, the mesh pouch shouldelute from about 30 mg to about 1000 mg of anesthetic over 1-10 days,including, e.g., about 30, 50, 100, 200, 400, 500, 750 or 1000 mg overthat time period.

The pouch should elute clinically effective amounts of anesthetic duringthe acute post-operative period when pain is most noticeable to thepatient. This period, defined in several clinical studies, tends to befrom 12 hours to 5 days after the operation, with pain greatest around24 hours and subsiding over a period of several days thereafter. Priorto 12 hours, the patient is usually still under the influence of anylocal anesthetic injection given during the surgery itself. After the5-day period, most of the pain related to the surgery itself (i.e.,incisional pain and manipulation of fascia, muscle, & nerves) hasresolved to a significant extent.

Bupivacaine has a known toxicity profile, duration of onset, andduration of action. Drug monographs recommend the daily dose not toexceed 400 mg. Those of skill in the art can determine the amount ofanesthetic to include in a polymer coating or a hydrogel coating toachieve the desired amount and duration of pain relief. Moreover,anesthetics that contain amines, such as lidocaine and bupivacaine, arehydrophobic and are difficult to load in sufficient amounts into themost commonly used plastics employed in the medical device industry,such as polypropylene and other non-resorbable thermoplastics. When intheir hydrochloride salt form, anesthetics cannot be effectively loadedin significant concentration into such non-resorbable thermoplasticsbecause of the mismatch in hydrophilicity of the two materials.

There are numerous reports of reduction or complete elimination ofnarcotic use and pain scores after open hernia repair during days 2-5with concomitant use of catheter pain pump system. In these cases, thepump delivers either a 0.25% or 0.5% solution of bupivacaine to thesubfascial area (Sanchez, 2004; LeBlanc, 2005; and Lau, 2003). At a 2mL/hour flow rate, this translates into constant “elution” ofapproximately 120 mg of bupivacaine per day. However, this systempurportedly suffers from leakage, so the 120 mg per day may only serveas an extremely rough guide for the amount of bupivacaine that should bedelivered to provide adequate post-operative pain relief.

One of the most well characterized sustained release depot systems forpost-operative pain relief reported in the literature is a PLGAmicrosphere-based sustained release formulation of bupivacaine. Thisformulation was developed and tested in humans for relief ofsubcutaneous pain as well as neural blocks. Human trials indicated thatsubcutaneous pain was relieved via injection of between 90 to 180 mg ofbupivacaine which then eluted into the surrounding tissue over a 7-dayperiod, with higher concentrations in the initial 24-hour periodfollowed by a gradual taper of the concentration. Other depotsustained-release technologies have successfully suppressedpost-operative pain associated with inguinal hernia repair. For example,external pumps and PLGA microsphere formulations have each purportedlyrelease drug for approximately 72 hours.

To achieve loading at the lower limit of the elution profile, forexample, one can choose a relatively hydrophilic biodegradable polymerand combine it with the anesthetic hydrochloride salt so that theanesthetic dissolves in the polymer at a concentration below theanesthetic's saturation limit. Such a formulation provides non-burstrelease of anesthetic. To achieve loading at the upper limit of theelution profile, one can spray coat a layer of an anesthetic-polymermixture that contains the anesthetic at a concentration above itssaturation limit. In this formulation, the polymer does not act as acontrol mechanism for release of the anesthetic, but rather acts as abinder to hold the non-dissolved, anesthetic particles together andalters the crystallization kinetics of the drug. A second coating layer,which may or may not contain further anesthetic, is sprayed on top ofthe first layer. When present in the second coating, the anestheticconcentration is at a higher ratio of polymer to anesthetic, e.g., aconcentration at which the anesthetic is soluble in the polymer layer.

The top layer thus can serve to control the release of the drug in thebottom layer (aka depot layer) via the drug-polymer solubility ratio.Moreover, it is possible to alter the release rate of the drug bychanging the thickness of the polymer layer and changing the polymercomposition according to its water uptake. A polymer that absorbs asignificant amount of water within 24 hours will release the contents ofthe depot layer rapidly. However, a polymer with limited water uptake orvariable water uptake (changes as a function of its stage ofdegradation) will retard release of the water soluble anesthetic agent.

In one embodiment, the biodegradable polymer coating releases drug forat least 2-3 days. Such release is preferred, for example, when the drugis an analgesic to aide in localized pain management at the surgicalsite. To achieve an analgesic affect, the anesthetic and/or analgesicshould be delivered to the injured tissue shortly after surgery ortissue injury.

In another embodiment, the coating comprises an anesthetic such that theanesthetic elutes from the implanted coated mesh to the surroundingtissue of the surgical site for between 1 and 10 days, which typicallycoincides with the period of acute surgical site pain. In anotherembodiment, delivery of an antimicrobial drug via a mesh of theinvention can create an inhibition zone against bacterial growth andcolonization surrounding the implant during the healing process (e.g.,usually about 7-30 days or less) and/or prevent undue fibroticresponses.

Using biodegradable polymer coatings avoids the issue of drugsolubility, impregnation or adherence in or to the underlying devicesince a coating having suitable chemical properties can be depositedonto the mesh pouch, optionally in concert with one or more drugs, toprovide for the release of relatively high concentrations of those drugsover extended periods of time. For example, by modulating the chemicalcomposition of the biodegradable polymer coating and the coatingmethodology, a clinically-efficacious amount of anesthetic drug can beloaded onto a mesh pouch to assure sufficient drug elution and toprovide surgical site, post-operative pain relief for the patient.

Other elution profiles, with faster or slower drug release over adifferent (longer or shorter) times, can be achieved by altering thethickness of the layers, the amount of drug in the depot layer and thehydrophilicity of the biodegradable polymer.

Biodegradable Polymers

The coatings on the pouches of the invention are formed frombiodegradable polymeric layers that optionally contain one or moredrugs. Methods of making biodegradable polymers are well known in theart.

The biodegradable polymers suitable for use in the invention include butare not limited to:

polylactic acid, polyglycolic acid and copolymers and mixtures thereofsuch as poly(L-lactide) (PLLA), poly(D,L-lactide)(PLA), polyglycolicacid [polyglycolide (PGA)], poly(L-lactide-co-D,L-lactide) (PLLA/PLA),poly(L-lactide-co-glycolide)(PLLA/PGA), poly(D,L-lactide-co-glycolide)(PLA/PGA), poly(glycolide-co-trimethylene carbonate) (PGA/PTMC),poly(D,L-lactide-co-caprolactone)(PLA/PCL) andpoly(glycolide-co-caprolactone) (PGA/PCL);

polyethylene oxide (PEO), polydioxanone (PDS), polypropylene fumarate,poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), polycaprolactone (PCL),polycaprolactone co-butylacrylate, polyhydroxybutyrate (PHBT) andcopolymers of polyhydroxybutyrate, poly(phosphazene), poly(phosphateester), poly(amino acid), polydepsipeptides, maleic anhydridecopolymers, polyiminocarbonates, poly[(97.5% dimethyl-trimethylenecarbonate)-co-(2.5% trimethylene carbonate)], poly(orthoesters),tyrosine-derived polyarylates, tyrosine-derived polycarbonates,tyrosine-derived polyiminocarbonates, tyrosine-derived polyphosphonates,polyethylene oxide, polyethylene glycol, polyalkylene oxides,hydroxypropylmethylcellulose, polysaccharides such as hyaluronic acid,chitosan and regenerate cellulose, and proteins such as gelatin andcollagen, and mixtures and copolymers thereof, among others as well asPEG derivatives or blends of any of the foregoing.

In some embodiments, biodegradable polymers of the invention havediphenol monomer units that are copolymerized with an appropriatechemical moiety to form a polyarylate, a polycarbonate, apolyiminocarbonate, a polyphosphonate or any other polymer.

The preferred biodegradable polymers are tyrosine-based polyarylatesincluding those described in U.S. Pat. Nos. 4,980,449; 5,099,060;5,216,115; 5,317,077; 5,587,507; 5,658,995; 5,670,602; 6,048,521;6,120,491; 6,319,492; 6,475,477; 6,602,497; 6,852,308; 7,056,493;RE37,160E; and RE37,795E; as well as those described in U.S. PatentApplication Publication Nos. 2002/0151668; 2003/0138488; 2003/0216307;2004/0254334; 2005/0165203; and those described in PCT Publication Nos.WO99/52962; WO 01/49249; WO 01/49311; WO03/091337. These patents andpublications also disclose other polymers containing tyrosine-deriveddiphenol monomer units or other diphenol monomer units, includingpolyarylates, polycarbonates, polyiminocarbonates, polythiocarbonates,polyphosphonates and polyethers.

Likewise, the foregoing patents and publications describe methods formaking these polymers, some methods of which may be applicable tosynthesizing other biodegradable polymers. Finally, the foregoingpatents and publications also describe blends and copolymers withpolyalkylene oxides, including polyethylene glycol (PEG). All suchpolymers are contemplated for use in the present invention.

The representative structures for the foregoing polymers are provide inthe above-cited patents and publications which are incorporated hereinby reference.

As used herein, DTE is the diphenol monomer desaminotyrosyl-tyrosineethyl ester; DTBn is the diphenol monomer desaminotyrosyl-tyrosinebenzyl ester; DT is the corresponding free acid form, namelydesaminotyrosyl-tyrosine. BTE is the diphenol monomer 4-hydroxy benzoicacid-tyrosyl ethyl ester; BT is the corresponding free acid form, namely4-hydroxy benzoic acid-tyrosine.

P22 is a polyarylate copolymer produced by condensation of DTE withsuccinate. P22-10, P22-15, P22-20, P22-xx, etc., represents copolymersproduced by condensation of (1) a mixture of DTE and DT using theindicated percentage of DT (i.e., 10, 15, 20 and xx % DT, etc.) with (2)succinate.

Additional preferred polyarylates are copolymers ofdesaminotyrosyl-tyrosine (DT) and an desaminotyrosyl-tyrosyl ester (DTester), wherein the copolymer comprises from about 0.001% DT to about80% DT and the ester moiety can be a branched or unbranched alkyl,alkylaryl, or alkylene ether group having up to 18 carbon atoms, anygroup of which can, optionally have a polyalkylene oxide therein.Similarly, another group of polyarylates are the same as the foregoingbut the desaminotyrosyl moiety is replaced by a 4-hydroxybenzoyl moiety.Preferred DT or BT contents include those copolymers with from about 1%to about 30%, from about 5% to about 30% from about 10 to about 30% DTor BT. Preferred diacids (used informing the polyarylates) includesuccinate, glutarate and glycolic acid.

Additional biodegradable polymers useful for the present invention arethe biodegradable, resorbable polyarylates and polycarbonates disclosedin U.S. provisional application Ser. No. 60/733,988, filed Nov. 3, 2005and in its corresponding PCT Appln. No. PCT/US06/42944, filed Nov. 3,2006. These polymers, include, but are not limited to, BTE glutarate,DTM glutarate, DT propylamide glutarate, DT glycineamide glutarate, BTEsuccinate, BTM succinate, BTE succinate PEG, BTM succinate PEG, DTMsuccinate PEG, DTM succinate, DT N-hydroxysuccinimide succinate, DTglucosamine succinate, DT glucosamine glutarate, DT PEG ester succinate,DT PEG amide succinate, DT PEG ester glutarate and DT PEG estersuccinate.

The most preferred polyarylates are the DTE-DT succinate family ofpolymers, e.g., the P22-xx family of polymers having from 0-50%, 5-50%,5-40%, 1-30% or 10-30% DT, including but not limited to, about 1, 2, 5,10, 15, 20, 25, 27.5, 30, 35, 40%, 45% and 50% DT.

Additionally, the polyarylate polymers used in the present invention canhave from 0.1-99.9% PEG diacid to promote the degradation process asdescribed in U.S. provisional application Ser. No. 60/733,988. Blends ofpolyarylates or other biodegradable polymers with polyarylates are alsopreferred.

Drugs

Any drug, biological agent or active ingredient compatible with theprocess of preparing the mesh pouches of the invention can beincorporated into one or more layers of the biodegradable polymericcoatings on the mesh. Doses of such drugs and agents are know in theart. Those of skill in the art can readily determine the amount of aparticular drug to include in the coatings on the meshes of theinvention.

Examples of drugs suitable for use with the present invention includeanesthetics, antibiotics (antimicrobials), anti-inflammatory agents,fibrosis-inhibiting agents, anti-scarring agents, leukotrieneinhibitors/antagonists, cell growth inhibitors and the like. As usedherein, “drugs” is used to include all types of therapeutic agents,whether small molecules or large molecules such as proteins, nucleicacids and the like. The drugs of the invention can be used alone or incombination.

Any pharmaceutically acceptable form of the drugs of the presentinvention can be employed in the present invention, e.g., the free baseor a pharmaceutically acceptable salt or ester thereof. Pharmaceuticallyacceptable salts, for instance, include sulfate, lactate, acetate,stearate, hydrochloride, tartrate, maleate, citrate, phosphate and thelike.

Examples of non-steroidal anti-inflammatories include, but are notlimited to, naproxen, ketoprofen, ibuprofen as well as diclofenac;celecoxib; sulindac; diflunisal; piroxicam; indomethacin; etodolac;meloxicam; r-flurbiprofen; mefenamic; nabumetone; tolmetin, and sodiumsalts of each of the foregoing; ketorolac bromethamine; ketorolacbromethamine tromethamine; choline magnesium trisalicylate; rofecoxib;valdecoxib; lumiracoxib; etoricoxib; aspirin; salicylic acid and itssodium salt; salicylate esters of alpha, beta, gamma-tocopherols andtocotrienols (and all their d, 1, and racemic isomers); and the methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, esters ofacetylsalicylic acid.

Examples of anesthetics include, but are not limited to, licodaine,bupivacaine, and mepivacaine. Further examples of analgesics,anesthetics and narcotics include, but are not limited to acetaminophen,clonidine, benzodiazepine, the benzodiazepine antagonist flumazenil,lidocaine, tramadol, carbamazepine, meperidine, zaleplon, trimipraminemaleate, buprenorphine, nalbuphine, pentazocain, fentanyl, propoxyphene,hydromorphone, methadone, morphine, levorphanol, and hydrocodone. Localanesthetics have weak antibacterial properties and can play a dual rolein the prevention of acute pain and infection.

Examples of antimicrobials include, but are not limited to, triclosan,chlorhexidine, rifampin, minocycline (or other tetracyclinederivatives), vancomycin, gentamycine, cephalosporins and the like. Inpreferred embodiments the coatings contain rifampin and anotherantimicrobial agent, preferably that agent is a tetracycline derivative.In another preferred embodiment, the coatings contains a cephalosporinand another antimicrobial agent. Preferred combinations include rifampinand minocycline, rifampin and gentamycin, and rifampin and minocycline.

Further antimicrobials include aztreonam; cefotetan and its disodiumsalt; loracarbef; cefoxitin and its sodium salt; cefazolin and itssodium salt; cefaclor; ceftibuten and its sodium salt; ceftizoxime;ceftizoxime sodium salt; cefoperazone and its sodium salt; cefuroximeand its sodium salt; cefuroxime axetil; cefprozil; ceftazidime;cefotaxime and its sodium salt; cefadroxil; ceftazidime and its sodiumsalt; cephalexin; cefamandole nafate; cefepime and its hydrochloride,sulfate, and phosphate salt; cefdinir and its sodium salt; ceftriaxoneand its sodium salt; cefixime and its sodium salt; cefpodoxime proxetil;meropenem and its sodium salt; imipenem and its sodium salt; cilastatinand its sodium salt; azithromycin; clarithromycin; dirithromycin;erythromycin and hydrochloride, sulfate, or phosphate saltsethylsuccinate, and stearate forms thereof, clindamycin; clindamycinhydrochloride, sulfate, or phosphate salt; lincomycin and hydrochloride,sulfate, or phosphate salt thereof, tobramycin and its hydrochloride,sulfate, or phosphate salt; streptomycin and its hydrochloride, sulfate,or phosphate salt; vancomycin and its hydrochloride, sulfate, orphosphate salt; neomycin and its hydrochloride, sulfate, or phosphatesalt; acetyl sulfisoxazole; colistimethate and its sodium salt;quinupristin; dalfopristin; amoxicillin; ampicillin and its sodium salt;clavulanic acid and its sodium or potassium salt; penicillin G;penicillin G benzathine, or procaine salt; penicillin G sodium orpotassium salt; carbenicillin and its disodium or indanyl disodium salt;piperacillin and its sodium salt; ticarcillin and its disodium salt;sulbactam and its sodium salt; moxifloxacin; ciprofloxacin; ofloxacin;levofloxacins; norfloxacin; gatifloxacin; trovafloxacin mesylate;alatrofloxacin mesylate; trimethoprim; sulfamethoxazole; demeclocyclineand its hydrochloride, sulfate, or phosphate salt; doxycycline and itshydrochloride, sulfate, or phosphate salt; minocycline and itshydrochloride, sulfate, or phosphate salt; tetracycline and itshydrochloride, sulfate, or phosphate salt; oxytetracycline and itshydrochloride, sulfate, or phosphate salt; chlortetracycline and itshydrochloride, sulfate, or phosphate salt; metronidazole; dapsone;atovaquone; rifabutin; linezolide; polymyxin B and its hydrochloride,sulfate, or phosphate salt; sulfacetamide and its sodium salt; andclarithromycin.

Examples of antifungals include amphotericin B; pyrimethamine;flucytosine; caspofungin acetate; fluconazole; griseofulvin; terbinafinand its hydrochloride, sulfate, or phosphate salt; ketoconazole;micronazole; clotrimazole; econazole; ciclopirox; naftifine; anditraconazole.

Other drugs that can be incorporated into the coatings on the meshpouches of the invention include, but are not limited to, keflex,acyclovir, cephradine, malphalen, procaine, ephedrine, adriamycin,daunomycin, plumbagin, atropine, quinine, digoxin, quinidine,biologically active peptides, cephradine, cephalothin,cis-hydroxy-L-proline, melphalan, penicillin V, aspirin, nicotinic acid,chemodeoxycholic acid, chlorambucil, paclitaxel, sirolimus,cyclosporins, 5-fluorouracil and the like.

Additional, drugs include those that act as angiogenensis inhibitors orinhibit cell growth such as epidermal growth factor, PDGF, VEGF, FGF(fibroblast growth factor) and the like. These drugs include anti-growthfactor antibodies (neutrophilin-1), growth factor receptor-specificinhibitors such as endostatin and thalidomide. Examples of usefulproteins include cell growth inhibitors such as epidermal growth factor.

Examples of anti-inflammatory compound include, but are not limited to,anecortive acetate; tetrahydrocortisol, 4,9(11)-pregnadien-17.alpha.,21-diol-3,20-dione and its -21-acetate salt; 111-epicortisol;17.alpha.-hydroxyprogesterone; tetrahydrocortexolone; cortisona;cortisone acetate; hydrocortisone; hydrocortisone acetate;fludrocortisone; fludrocortisone acetate; fludrocortisone phosphate;prednisone; prednisolone; prednisolone sodium phosphate;methylprednisolone; methylprednisolone acetate; methylprednisolone,sodium succinate; triamcinolone; triamcinolone-16,21-diacetate;triamcinolone acetonide and its -21-acetate, -21-disodium phosphate, and-21-hemisuccinate forms; triamcinolone benetonide; triamcinolonehexacetonide; fluocinolone and fluocinolone acetate; dexamethasone andits -21-acetate, -21-(3,3-dimethylbutyrate), -21-phosphate disodiumsalt, -21-diethylaminoacetate, -21-isonicotinate, -21-dipropionate, and-21-palmitate forms; betamethasone and its -21-acetate, -21-adamantoate,-17-benzoate, -17,21-dipropionate, -17-valerate, and -21-phosphatedisodium salts; beclomethasone; beclomethasone dipropionate;diflorasone; diflorasone diacetate; mometasone furoate; andacetazolamide.

Examples of leukotriene inhibitors/antagonists include, but are notlimited to, leukotriene receptor antagonists such as acitazanolast,iralukast, montelukast, pranlukast, verlukast, zafirlukast, andzileuton.

Another useful drug that can be incorporated into the coatings of theinvention is sodium 2-mercaptoethane sulfonate (Mesna). Mesna has beenshown to diminish myofibroblast formation in animal studies of capsularcontracture with breast implants [Ajmal et al. (2003) Plast. Reconstr.Surg. 112:1455-1461] and may thus act as an anti-fibrosis agent.

Those of ordinary skill in the art will appreciate that any of theforegoing disclosed drugs can be used in combination or mixture incoatings of the present invention.

Coating Methods

In accordance with the invention, one method to coat the mesh with astiffening agent is to spray a solution of polymer to coat the filamentsor fibers of the mesh to temporarily immobilize contact points of thefilaments or fibers of said mesh. This method comprises (a) preparing acoating solution comprising a solvent and the stiffening agent; (b)spraying a mesh one or more times to provide an amount of solution onthe mesh to produce a coating having a thickness and placementsufficient to temporarily immobilize contact points of the filaments orfibers of the mesh that coats filaments or fibers; and (c) drying themesh to produce said coating. An example of ratio of coating thicknessto polymer coating is shown in the scanning electron micrograph of FIG.7. When used with a drug (or combination of drugs), the drug is includedin the coating solution at the desired concentration.

Spraying can be accomplished by known methods. For example, the coatingcan be applied to the entire mesh or to that portion of the meshnecessary to stiffen it. One technique is to dip the mesh in the coatingmaterial; another is to push the mesh through rollers that transfer thecoating on the mesh. Spraying the mesh with a microdroplets is alsoeffective. Techniques for selectively coating only those areas necessaryto stiffen the mesh include deposition the coating through a template ormask that exposes only the desired areas of coverage for the coating,including dispensing the coating with micro needles or similar means.More preferably the coating can be applied using a photoresist-like maskthat expose the desired portions, applying the coating over thephotomask and the removing the photomask.

The coated meshes can be laser cut to produce the desired shaped andsized pouches, coverings and the like. The pouches can be shaped to fitrelatively snugly or more loosely around the implantable medical device.Two pieces can be sealed, by heat, by ultrasound or other method knownin the art, leaving one side open to permit insertion of the device atthe time of the surgical procedure and to allow the leads or other wiresto extend out of the pouch stick out/protrude.

Additionally, the mesh pouches of the invention have a space or openingsufficient to allow the leads from the device to pass through the pouch.The number of spaces or opening in the pouch that are provided can matchthe number and placement of the leads or other tubes extending from theCRM or other IMD, as applicable for the relevant device.

In preferred embodiments, the shape and size of the pouch of theinvention is similar to that of the CRM or IMD with which it is beingused, and the pouch has a sufficient number of openings or spaces toaccommodate the leads or tubings of the particular CRM or other IMD.

The pouches of the invention are porous from the mesh but can haveadditional porosity. For example, additional porosity can be imparted bylaser cutting additional holes in the coated. mesh Porous pouches Hence,the pouch need not completely encase or surround the IMD. An IMD is thussubstantially encapsulated, encased, surrounded or covered when thepouch can hold the device and at least 20%, 30%, 50%, 60%, 75%, 80%,85%, 90%, 95% or 98% of the device is within the pouch. Porous pouchesand partially encased pouches permit contact with tissue and body fluidsand are particularly useful with monopole CRM or other IMD devices.Porosity will contribute to the percentage of the IMD covered by thepouch. That is, an IMD is considered to be 50% covered if it iscompletely surrounded by a pouch that is constructed of a film with 50%voids or holes.

CRMs and Other IMDs

The CRMs and other IMDs used with the pouches of the invention includebut are not limited to pacemakers, defibrillators, implantable accesssystems, neurostimulators, other stimulation devices, ventricular assistdevices, infusion pumps or other implantable devices (or implantablecomponents thereof) for delivering medication, hydrating solutions orother fluids, intrathecal delivery systems, pain pumps, or any otherimplantable system to provide drugs or electrical stimulation to a bodypart.

Implantable cardiac rhythm management devices (CRMs) are a form of IMDsand are life-long medical device implants. CRMs ensure the heartcontinually beats at a steady rate. There are two main types of CRMdevices: implantable cardiac rhythm management devices and implantabledefibrillators.

The ICDs, or implantable cardioverter defibrillator, and pacemakersshare common elements. They are permanent implants inserted throughrelatively minor surgical procedures. Each has 2 basic components: agenerator and a lead. The generator is usually placed in a subcutaneouspocket below the skin of the breastbone and the lead is threaded downand into the heart muscle or ventricle. The common elements of placementand design result in shared morbidities, including lead extrusion,lead-tip fibrosis, and infection. Although infection rates arepurportedly quite low, infection is a serious problem as any bacterialcontamination of the lead, generator, or surgical site can traveldirectly to the heart via bacterial spreading along the generator andleads. Endocarditis, or an infection of the heart, has reportedmortality rates as high as 33%.

An ICD is an electronic device that constantly monitors heart rate andrhythm. When it detects a fast, abnormal heart rhythm, it deliversenergy to the heart muscle. This action causes the heart to beat in anormal rhythm again in an attempt to return it to a sinus rhythm.

The ICD has two parts: the lead(s) and a pulse generator. The lead(s)monitor the heart rhythm and deliver energy used for pacing and/ordefibrillation (see below for definitions). The lead(s) are directlyconnected to the heart and the generator. The generator houses thebattery and a tiny computer. Energy is stored in the battery until it isneeded. The computer receives information on cardiac function via theleads and reacts to that information on the basis of its programming.

The different types of ICDs include, but are not limited to, singlechamber ICDs in which a lead is attached in the right ventricle. Ifneeded, energy is delivered to the ventricle to help it contractnormally; dual chamber ICDs in which the leads are attached in the rightatrium and the right ventricle. Energy is delivered first to the rightatrium and then to the right ventricle to ensure that the heart beats ina normal sequence; and biventricular ICDs in which leads are attached inthe right atrium, the right ventricle and the left ventricle. Thisarrangement helps the heart beat in a more balanced way and isspecifically used for patients with heart failure.

A pacemaker is a small device that sends electrical impulses to theheart muscle to maintain a suitable heart rate and rhythm. A pacemakercan also be used to treat fainting spells (syncope), congestive heartfailure, and hypertrophic cardiomyopathy. Pacemakers are generallyimplanted under the skin of the chest during a minor surgical procedure.The pacemaker is also comprised of leads and a battery-driven pulsegenerator. The pulse generator resides under the skin of the chest. Theleads are wires that are threaded through the veins into the heart andimplanted into the heart muscle. They send impulses from the pulsegenerator to the heart muscle, as well as sense the heart's electricalactivity.

Each impulse causes the heart to contract. The pacemaker may have one tothree leads, depending on the type of pacemaker needed to treat yourheart problem.

The different types of pacemakers include, but are not limited to singlechamber pacemakers which use one lead in the upper chambers (atria) orlower chambers (ventricles) of the heart; dual chamber pacemakers whichuse one lead in the atria and one lead in the ventricles of your heart;and biventricular pacemakers which use three leads: one placed in theright atrium, one placed in the right ventricle, and one placed in theleft ventricle (via the coronary sinus vein).

The pouches of the invention can thus be designed to fit a wide range ofpacemakers and implantable defibrillators from a variety ofmanufacturers (see Table 1). Sizes of the CRMs vary and typically sizeranges are listed in Table 1.

TABLE 1 CRM Devices Size Manufacturer Device Type Model (H″ × L″ × W″)Medtronic EnPulse Pacing Pacing system E2DR01 1.75 × 2 × 0.33 systemMedtronic EnPulse Pacing Pacing system E2DR21 1.75 × 1.63 × 0.33 systemMedtronic EnRhythm Pacing system P1501DR 1.77 × 2 × 0.31 Pacing systemMedtronic AT500 Pacing Pacing system AT501 1.75 × 2.38 × 0.33 systemMedtronic Kappa DR900 Pacing system DR900, DR700 1.75-2 × 1.75-2 × 0.33& 700 series Medtronic Kappa DR900 Pacing system SR900, SR700 1.5-1.75 ×1.75-2 × 0.33 & 700 series Medtronic Sigma Pacing system D300, D200,D303, 1.75 × 2 × 0.33 D203 Medtronic Sigma Pacing system DR300, DR200,1.75-2 × 2 × 0.33 DR303, DR306, DR203 Medtronic Sigma Pacing systemVDD300, VDD303 1.75 × 1.75 × 0.33 Medtronic Sigma Pacing system S300,S200, S100, 1.63 × 2 × 0.33 S303, S203, S103, S106, VVI-103 MedtronicSigma SR Pacing system SR300, S200, 1.63 × 2 × 0.33 SR303, SR306, SR203Medtronic Entrust Defibrillator D154VRC 35J 2.44 × 2 × 0.6 MedtronicMaximo & Defibrillator Size of a pager Marquis family Medtronic Gemfamily Defibrillator III T, III R, III R, II Size of a pager R, II VRGuidant Contak Rnewal Pacing system H120, H125 2.13 × 1.77 × 033 TR St.Jude Identity Pacing system ADx DR, ADx SR, 1.6-1.73 × 1.73-2.05 × 0.24ADx XL, ADx VDR St. Jude Integrity Pacing system ADx DR, ADx SR 1.6-1.73× 1.73-2.05 × 0.24

Implantable neurostimulators are similar to pacemakers in that thedevices generate electrical impulses. These devices send electricalsignals via leads to the spine and brain to treat pain and otherneurological disorders. For example, when the leads are implanted in thespine, the neurostimulation can be used to treat chronic pain(especially back and spinal pain); when the leads are implanted in thebrain, the neurostimulation can be used to treat epilepsy and essentialtremor including the tremors associated with Parkinson's disease andother neurological disorders. Neurostimulation can be used to treatsevere, chronic nausea and vomiting as well as urological disorders. Forthe former, electrical impulses are sent to the stomach; for the latter,the electrical impulses are sent to the sacral nerves in the lower back.The implant location of the neurostimulator varies by application but,in all cases, is placed under the skin and is susceptible to infectionat the time of implantation and pos-implantation. Likewise,reintervention and replacement of batteries in the neurostimulators canoccur at regular intervals.

The pouches of the invention can thus be designed to fit a wide range ofneurostimulators from a variety of manufacturers (see Table 2). Sizes ofthe neurostimulators vary and typically size ranges are listed in Table2.

TABLE 2 Neurostimulators Manufacturer Device Type Model Size (H″ × L″ ×W″) Medtronic InterStim Neurostimulation 3023 2.17 × 2.4 × 0.39 INSMedtronic InterStim Neurostimulation 3058 1.7 × 2.0 × 0.3 INS IIMedtronic RESTORE Neurostimulation 37711 2.56 × 1.93 × 0.6 AdvancedPrecision Neurostimulation/Spinal 2.09 × 1.70 × 0.35 Bionics IPG CordStimulator (Boston Scientific) Cyberonics VNS Neurostimulation/Epilepsy102 2.03 × 2.06 × 0.27 Therapy system Cyberonics VNSNeurostimulation/Epilepsy 102R 2.03 × 2.32 × 0.27 Therapy system ANS(St. Jude) Eon Neurostimulation Comparable to Medtronic Restore ANS (St.Jude) Genesis RC Neurostimulation Comparable to Medtronic Restore ANS(St. Jude) Genesis XP Neurostimulation Comparable to Medtronic Restore

Reported infection rates for first implantation are usually quite low(less than 1%); however, they increase dramatically when areintervention is necessary. Reintervention often requires the removalof the generator portion of the ICD, pacemaker, neurostimulator, drugpump or other IMD and having a resorbable pouch enhances that process.

Other IMDs for use in the invention are drug pumps, especially painpumps and intrathecal delivery systems. These devices generally consistof an implantable drug pump and a catheter for dispensing the drug. Theimplantable drug pump is similar in size to the neurostimulators andCRMs. Further implantable medical devices include, but are not limitedto, implantable EGM monitors, implantable access systems, or any otherimplantable system that utilizes battery power to provide drugs orelectrical stimulation to a body part.

Antimicrobial Efficacy

Antimicrobial efficacy of the pouches of the invention can bedemonstrated in laboratory (in vitro), for example, using the modifiedKirby-Bauer Antibiotic Susceptibility Test (Disk Diffusion Test) (invitro) to assess bacterial zones of inhibitions or by the Boburden TestMethod (in vitro). In such experiments, a small disk of the pouch is cutand used, Antimicrobial efficacy can also be demonstrated in vivo usinganimal models of infection. For example, a pouch and device combinationare implanted in an animal, the surgical site is deliberately infectedwith a pathogenic microorganism, such as Staphylococcus aureus orStaphylococcus epidermis, and the animal is monitored for signs ofinfection and inflammation. At sacrifice, the animal is assessed forinflammation, fibrosis and bacterial colonization of the pouch, deviceand the surrounding tissues.

It will be appreciated by those skilled in the art that variousomissions, additions and modifications may be made to the inventiondescribed above without departing from the scope of the invention, andall such modifications and changes are intended to fall within the scopeof the invention, as defined by the appended claims. All references,patents, patent applications or other documents cited are hereinincorporated by reference in their entirety.

Example 1 Antibiotic Release from DTE-DT Succinate Coated Mesh

A. Preparation of Mesh by Spray-Coating

A 1% solution containing a ratio of 1:1:8 rifampin:minocycline:polymerin 9:1 tetrahydrofuran/methanol was spray-coated onto a surgical mesh byrepeatedly passing the spray nozzle over each side of the mesh untileach side was coated with at least 10 mg of antimicrobial-embeddedpolymer. Samples were dried for at least 72 hours in a vacuum ovenbefore use.

The polymers are the polyarylates P22-xx having xx being the % DTindicated in Table 3. In Table 3, Rxx or Mxx indicates the percentage byweight of rifampin (R) or minocycline (M) in the coating, i.e., R10M10means 10% rifampin and 10% minocycline hydrochloride with 80% of theindicated polymer. Table 3 provides a list of these polyarylates withtheir % DT content, exact sample sizes, final coating weights and drugcoating weights.

TABLE 3 Polyarylate Coated Meshes with Rifampin and Minocycline HCl Avg.Coating Coating Wt. Minocycline Sample Coating Parameters Wt. per 116cm² per cm² Rifampin HCl No. (No. Spray Passes) (mg) (mg) (μg) (μg) 1P22-25 R10M10 100 0.86 86 86 (20) 2 P22-25 R10M10 150 1.29 129 129 (40)3 P22-25 R10M10 200 1.72 172 172 (80) 4 P22-27.5 R10M10 20 0.17 17 17(1) 5 P22-27.5 R10M10 40 0.34 34 34 (2) 6 P22-27.5 R10M10 60 0.52 52 52(3)B. Zone of Inhibition (ZOI) Studies

The ZOI for antibiotic coated meshes was determined according to theKirby-Bauer method. Staphylococcus epidermidis or Staphylococcus aureuswere inoculated into Triplicate Soy Broth (TSB) from a stock culture andincubated at 37° C. until the turbidity reached McFarland #0.5 standard(1-2 hours). Plates were prepared by streaking the bacteria onto onMueller-Hinton II agar (MHA) three times, each time swabbing the platefrom left to right to cover the entire plate and rotating the platebetween swabbing to change direction of the streaks.

A pre-cut piece (1-2 cm²) of spray-coated mesh was firmly pressed intothe center of pre-warmed Mueller Hinton II agar plates and incubated at37° C. Pieces were transferred every 24 h to fresh, pre-warmed MuellerHinton II agar plates using sterile forceps. The distance from thesample to the outer edge of the inhibition zone was measured every 24 hand is reported on the bottom row in Table 4 and 5 for each sample. Thetop row for each sample represents difference between the diameter ofthe ZOI and the diagonal of the mesh. Table 4 shows the ZOI results formeshes placed on S. epidermidis lawns and Table 5 shows the ZOI resultsfor meshes placed on S. aureus lawns. Additionally, three pieces wereremoved every 24 h for analysis of residual minocycline and rifampin.

FIG. 1 shows the total ZOI on S. aureus for meshes with 10% each ofminocycline hydrochloride and rifampin in a DTE-DT succinate polyarylatecoating having 25% or 27.5% DT. The catheter is a COOK SPECTRUM venouscatheter impregnated with rifampin and minocycline hydrochloride.

TABLE 4 S. epidermidis ZOI Sample Day 1 Day 2 Day 3 Day 4 Day 6 Day 7No. Coating Parameters (mm) (mm) (mm) (mm) (mm) (mm) 1 P22-25 R10M1018.65 31.70 33.04 29.63 25.43 15.66 31.30 44.36 45.70 42.29 38.08 28.312 P22-25 R10M10 19.28 30.59 33.67 31.74 0.60 8.56 32.10 43.45 46.5344.60 13.45 21.42 3 P22-25 R10M10 26.59 34.70 30.31 31.75 23.65 17.2939.48 47.59 43.20 46.16 36.54 30.18 4 P22-27.5 R10M10 18.33 31.58 35.2530.45 2.08 6.72 31.06 44.31 47.98 43.18 14.81 19.45 5 P22-27.5 R10M1017.48 32.81 33.68 28.06 7.89 12.86 30.17 45.51 46.38 40.76 20.59 25.56 6P22-27.5 R10M10 31.73 29.81 35.03 24.99 12.55 16.22 44.42 42.50 47.7237.68 25.24 28.91

TABLE 5 S. aureus ZOI Sample Day 1 Day 2 Day 3 Day 4 Day 5 Day 7 No.Coating Parameters (mm) (mm) (mm) (mm) (mm) (mm) 1 P22-25 R10M10 12.7517.90 18.22 22.44 12.35 11.94 25.84 30.66 30.97 35.20 25.11 24.69 2P22-25 R10M10 14.23 11.28 20.04 28.24 16.31 10.35 26.90 23.94 32.7140.91 28.98 23.02 3 P22-25 R10M10 17.87 21.52 23.45 25.36 17.42 14.7230.57 34.22 36.15 36.02 30.12 27.42 4 P22-27.5 R10M10 9.77 19.02 19.0623.01 13.81 5.61 22.76 32.01 32.05 36.00 26.80 18.6 5 P22-27.5 R10M109.70 21.77 19.55 24.00 11.84 3.89 22.30 34.36 35.48 36.60 24.44 16.49 6P22-27.5 R10M10 20.92 21.29 22.40 24.27 11.06 4.99 33.68 34.05 35.1537.02 23.82 17.75

Table 6 shows that the duration of in vitro drug release increases withthe hydrophilicity of the resorbable polymer. Solvent cast films weresoaked in PBS and antibiotic release was monitored by HPLC.

TABLE 6 Antibiotic Release as a Function of Polymer Hydrophilicity Daysreleasing Days releasing Films Rifampin MinocyclineHCl P22-15 R10M10 3232 P22-20 R10M10 25 25 P22-25 R10M10 7 7 P22-27.5 R10M10 10 10 P22-30R10M10 4 4

Example 2 Bupivacaine Release from DTE-DT Succinate Coated Mesh

A. Preparation of Mesh

For the experiment shown in FIG. 2, a first depot coating containing 540mg of bupivacaine HCl as a 4% solution with 1% P22-27.5 polyarylate in amixture of THF Methanol was spray coated onto a mesh. A second layerconsisting of 425 mg of the same polyarylate alone was deposited on topof the first layer.

For the experiment shown in FIG. 3, a solution of approximately 4%bupivacaine in DTE-DT succinate polymer having 27.5% DT was sprayed ontoa mesh using the indicted number of passes followed by the indicatednumber of dips into a solution of the same polyarylate in THF:Methanol(9:1)

B. Anesthetic Release

Pre-weighed pieces of mesh were placed in PBS at 37° C. and a samplewithdrawn periodically for determination of bupivacaine by HPLC. FIG. 2shows the cumulative release of bupivacaine into PBS from the multilayerpolyarylate coating as a function of time. Nearly 80% of the bupivacainehad been released after 25 hours of incubation.

FIG. 3 is an example of the changes in release characteristics that canbe achieved by altering both the amount of drug in the depot layer andthe thickness of the outer layer. These coated surgical meshes are muchstiffer than their uncoated counterparts.

Example 3 In Vivo Bupivacaine Release from DTE-DT Succinate CoatedMeshes

A. Overview

Rats with jugular cannulas for pharmacokinetic studies were surgicallyimplanted with a 1×2 cm P22-27.5 polyarylate-coated mesh containing 7.5mg of bupivacaine/cm². Before surgery, baseline pin-prick responses tonociception were measured at the planned surgical incision site, andbaseline blood samples were obtained. A hernia was created by incisioninto the peritoneal cavity during via subcostal laparotomy, and aLichtenstein non-tension repair was performed using thebupivacaine-impregnated polyarylate-coated mesh. Blood samples weredrawn at 3, 6, 24, 48, 72, 96, and 120 hours after implantation. Priorto drawing blood, the rats were subjected to a pin prick test to assessdermal anesthesia from bupivacaine release. The behavioral resultsindicate that moderate levels of dermal anesthesia appeared from 3 to120 hours, with the amount at 6 and 48 hours significantly abovebaseline (p<0.05). Pharmacokinetic analysis indicates that the plasmabupivacaine levels fit a one-compartment model with first-orderabsorption from 0 to 24 hours.

B. Preparation of Surgical Mesh

A polypropylene mesh was spray coated as described in the firstparagraph of Example 2. Individual meshes were cut to 1×2 cm,individually packaged, and sterilized by gamma irradiation. The mesh wasloaded with 7.5 mg/cm² of bupivacaine HCl for a total of 15 mg ofbupivacaine loaded per 1×2 cm mesh.

C. Surgical Implantation of Mesh

Eight male rats, 59-63 days old and weighing from 250-275 g, wereobtained from Taconic Laboratory (Germantown, N.Y.) with an externaljugular cannula (SU007). Each rat was anesthetized with isoflurane to aplane of surgical anesthesia, as determined by the absence of a responseto toe pinch and corneal reflex and maintained at 2% isoflurane duringsurgery. The subcostal site was shaved, washed with 10% providone iodineand rinsed with 70% ethanol. Sterile drapes were used to maintain anaseptic surgical field, and sterilized instruments were re-sterilizedbetween rats using a hot-bead sterilizer. A 2.5 cm skin incision wasmade 0.5 cm caudal to and parallel to the last rib. The underlyingsubcutaneous space (1 cm on both sides of the incision) was loosened toaccommodate the mesh. A 2 cm incision was made through the muscle layersalong the same plane as the skin incision, penetrating the peritonealcavity and the peritoneum was closed with 6-0 Prolene sutures in acontinuous suture pattern. Rather than suturing the inner and outeroblique muscles using the classic “tension closure,” a Lichtenstein“non-tension” repair was undertaken using the mesh as the repairmaterial. The mesh prepared in Section A was positioned over theincisional hernia, and sutured into the internal and external obliquemuscles using 6-0 Prolene sutures. The subcutaneous tissue was thensutured in a continuous pattern with 6 to 8 6-0 Prolene sutures toprevent the rats from accessing the mesh, followed by 6 to 8 skinsutures. Total surgical time was 10 min for anesthetic induction andpreparation and 20 min for the surgery.

The rats were allowed to recover in their home cages, and monitoredpost-surgically until they awoke. Blood samples were drawn fordetermination of plasma bupivacaine levels at 3, 6, 24, 48, 72, 96, and120 hours after surgery. The rats were assessed for guarding theincision, and the incision was assessed for signs of inflammation,swelling or other signs of infection. No rats exhibited toxicity orseizures, or were in a moribund state from infection or the release ofbupivacaine.

D. Dermal Anesthetic Tests

The nociceptive pin prick test was used to assess dermal anesthesia(Morrow and Casey, 1983; Kramer et al., 1996; Haynes et al., 2000;Khodorova and Strichartz, 2000). Holding the rat in one hand, the otherhand was used to apply the pin. Nociception was indicated by askin-flinch or by a nocifensive (i.e., startle or attempt to escape)response from the rat. While the presence of the mesh interfered withthe skin flinch response, nocifensive response remained completelyintact.

Baseline nocifensive responses to 10 applications of the pin from a Buckneurological hammer were obtained at the planned incision site prior tomesh implantation. After surgery, the pin prick test was applied rostralto the incision. The nerves caudal to the incision were transectedduring the procedure, and therefore did not respond to pin applicationand were not tested. The post-implantation test was repeated using thesame force as before surgery and with 10 pin applications, and thepercent inhibition of nocifensive responding was calculated by: [1−(testresponses/10 base responses)]×100. The data was analyzed using repeatedmeasures ANOVA followed by post hoc analysis using the Tukey's test. Theresults are shown in FIG. 4.

Example 4 Mesh Stiffness

A. Meshes prepared as described in Example 1 were subject to stiffnesstesting according to the method of TyRx Pharma Inc. Mesh Stiffness TestProtocol, ATM 0410, based on ASTM 4032-94. Meshes were sealed in foilbags before sterilization using gamma irradiation. Where indicated by“Gamma N₂”, the bags were flushed with nitrogen before sealing andirradiation. Meshes were tested in triplicate. The results are shown inTable 7 and indicate that aging does not affect the flexibility of thecoated meshes.

TABLE 7 Stiffness Testing Sample 1 Sample 2 Sample 3 Average Mesh(Newtons) (Newtons) (Newtons) (Newtons) t-test PPM3, Gamma, 12 monthaged 1.84 2.36 1.62 1.94 0.016 coating PPM3, Gamma N₂ flush, 12 month2.2 2.24 2.56 2.3 0.014 aged coating Prolene, Ethylene oxide 2.78 2.161.94 2.29 0.019 sterilization PPM3, No Sterilization, 1.2 1.3 1 1.17 NoCoating

B. Meshes were prepared by spray coating a solution of P22-27.5 onto aPPM3 mesh as generally described in Example 1. the coated meshes werecut into 3″ by 3″ squares to provide 80 mg polymer coating per square.The squares were incubated in 1 L of 0.01 M PBS for the indicated timesthen removed for stiffness testing as described in part A of thisExample. All experiments were done in triplicate. As a control,non-coated PPM3 meshes were incubated under the same conditions. Thestiffness of the control when dry was 1.42±0.23 N when dry and 1.12 Nafter both 1 hour and 24 hour in 0.01 M PBS. The results are shown inFIG. 6.

Example 5 Micrographs of Coated Meshes

A tyrosine polyarylate-coated mesh without antibiotics, i.e., only apolymer coating, was prepared as described in Example 1 and omitting theantibiotics in the spray coating solution. An optical image of thecoated mesh is shown in the top left panel of FIG. 7 at a magnificationthat readily shows the woven nature of the mesh and the contact pointsof the filaments. A close up of a contact point is shown in the bottomleft panel of FIG. 7 and demonstrates that the coating immobilizes thecontact points of the mesh filaments. The right panel of FIG. 7 is ascanning electron micrograph of a coated filament.

FIG. 8 shows an optical image of a mesh from Example 1, i.e., coatedwith polymer, rifampin and minocycline. In color, this photograph showsthe mesh on a blue background with the filaments appearing greenish withsome orange and the knots (or filament contact points) appearing mostlysolid orange. The orange color is due to the antibiotics and is morevisible on the knots due to the greater surface area of the mesh in thatregion. The color differentiation is difficult to visualize in the blackand white version of this photograph so on the right panel the areas oforange are indicated by circled areas filled with diagonal lines.

Example 6 Antimicrobial, Coated Mesh, Pacemaker Pouch

The antimicrobial pacemaker pouch is a dual component (resorbable andnon-resorbable), sterile prosthesis designed to hold a pacemaker pulsegenerator or defibrillator to create a stable environment when implantedin the body. The pouch is constructed of a non-resorbable mesh comprisedof knitted filaments of polypropylene and a bioresorbable polyarylatecoating on the mesh containing the antimicrobial agents rifampin andminocycline. The antimicrobial agents are released for a minimum of 7days followed by full resorption of the polymer, leaving a light-weightpermanent mesh incorporated into the tissue and providing a stableenvironment for the pacemaker or defibrillator (see FIGS. 9 and 10).

The mesh for the pouch can be prepared in the same manner asantimicrobial polymer-coated surgical meshes described in U.S.provisional application 60/771,827, filed Feb. 8, 2006. The pouch isconstructed of two pieces of flat, coated mesh placed one on top of theother and sealed and cut into the shape using an ultrasonic weld. Thisresults in the formation of a pouch 2.5″×2.75″ in size, sealed onapproximately 3 and one-half sides, and coated with approximately 50 to75 mg of polymer and 6.1 mg of rifampin and 6.1 mg of minocycline (of86.11 μg/cm² for each drug). Such pouches can be designed to fit a widerange of pacemakers, implantable defibrillators, neurostimulators andother IMDs (see Table 1 and 2).

Antimicrobial Efficacy

Antimicrobial efficacy was demonstrated in laboratory (in vitro) and inanimal (in vivo) testing. Results indicate that coated mesh pouch iseffective in preventing microbial colonization of the mesh and generator(see Table 8).

Histological results from a dog study show that the pouch is rapidlyincorporated into the tissue surrounding the pacemaker, facilitating theformation of a stable environment for holding the pacemaker (FIG. 3).

TABLE 8 Antimicrobial Efficacy Antimicrobial Test Test Results DogImplantation Study No positive cultures (0/4) detected in the (in vivo)coated mesh pouch + generator implant sites compared with 100% positiveculture (4/4) for generator alone in response to a 5 × 10⁴ CFU inoculumof S. aureus Rabbit Implantation Significantly (p < 0.05) fewercolonized Study (in vivo)* mesh implants (16.6%) compared to Prolenemesh comparator (43.3%) in response to a 10⁵ CFU inoculum of S. aureus*Modified Kirby--Bauer ZOI > 10 mm for >7 days against to AntibioticSusceptibility S. aureus and S. epidermidis and Test (Disk DiffusionMRSA Test) (in vitro)* Boburden Test Method No growth to 10⁶ CFU/mL (invitro)* inoculum of S. aureus and, S. epidermidis after 7 daysincubation, and no growth to a 10⁸ CFU/mL inoculum of MRSA after 7 daysincubation* *Testing on antimicrobial mesh alone of the same composition

REFERENCES

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We claim:
 1. A mesh pouch prophylactically encasing at least about 75%of the surface of a medical device in said mesh pouch for implantationin the body, said mesh pouch comprising a porous surgical mesh which issufficiently porous to permit said medical device to be electricallygrounded to surrounding tissue and which permits tissue ingrowth intosaid mesh pouch which stabilizes said medical device within said meshpouch, said porous surgical mesh including one or more biodegradable andresorbable synthetic polymer coatings which have been applied to saidporous surgical mesh without substantially altering the porosity of saidsurgical mesh, whereby the stiffness of said surgical mesh is increasedto facilitate said implantation, but decreases subsequent to saidimplantation.
 2. The mesh pouch of claim 1, wherein said one or morecoatings temporarily stiffen said surgical mesh to at least 1.1 timesits original stiffness; and said one or more coatings comprises one ormore biodegradable polymers and one or more drugs which, alone or incombination, are capable of providing pain relief, inhibiting scarringor fibrosis and/or inhibiting bacterial growth.
 3. The mesh pouch ofclaim 1, wherein said one or more coatings comprise one or morebiodegradable polymers which act as a stiffening agent and coatfilaments or fibers of said surgical mesh to temporarily immobilizecontact points of the filaments or fibers of said mesh; and said one ormore coatings further comprise one or more drugs which, alone or incombination, are capable of providing pain relief, inhibiting scarringor fibrosis and/or inhibiting bacterial growth.
 4. The mesh pouch ofclaim 3, wherein said one or more coatings selectively and/or partiallycoat said filaments or said fibers.
 5. The mesh pouch of claim 3,wherein said contact points comprise the knots in a woven mesh.
 6. Themesh pouch of claim 2, wherein said one or more coatings increases thestiffness of said mesh by at least 1.1 to about 4.5 times its uncoatedstiffness.
 7. The mesh pouch of claim 1, wherein said mesh compriseswoven polypropylene.
 8. The mesh pouch of claim 1, wherein said one ormore biodegradable polymers are selected from the group consisting of apolylactic acid, polyglycolic acid, poly(L-lactide), poly(D,L-lactide),polyglycolic acid, poly(L-lactide-co-D,L-lactide),poly(L-lactide-co-glycolide), poly(D, L-lactide-co-glycolide),poly(glycolide-co-trimethylene carbonate),poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone),polyethylene oxide, polyoxaester, polydioxanone, polypropylene fumarate,poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), polycaprolactone,polycaprolactone cobutylacrylate, polyhydroxybutyrate,poly(phosphazene), poly(phosphate ester), poly(amino acid),polydepsipeptide, maleic anhydride copolymer, polyiminocarbonates,poly[(97.5% dimethyltrimethylene carbonate)-co-(2.5% trimethylenecarbonate)], poly(orthoesters), tyrosine-derived polyarylate,tyrosine-derived polycarbonate, tyrosine-derived polyiminocarbonate,tyrosine-derived polyphosphonate, polyalkylene oxide,hydroxypropylmethylcellulose, and copolymers, terpolymers and blends ofany thereof.
 9. The mesh pouch of claim 1, wherein at least one of saidbiodegradable polymers comprise one or more tyrosine-derived diphenolmonomer units.
 10. The mesh pouch of claim 9, wherein said polymer is apolyarylate.
 11. The mesh pouch of claim 10, wherein said polyarylate is(desaminotyrosyl-tyrosine) DT-desaminotyrosyl-tyrosine ethyl ester) DTEsuccinate having from about 1% DT to about 30% DT.
 12. The mesh pouch ofclaim 10, wherein said polyarylate is a random copolymer ofdesaminotyrosyl-tyrosine (DT) and an desaminotyrosyl-tyrosyl ester (DTester), wherein said copolymer comprises from about 0.001% DT to about80% DT and said ester moiety can be a branched or unbranched alkyl,alkylaryl, or alkylene ether group having up to 18 carbon atoms, any ofgroup of which can, optionally have a polyalkylene oxide therein. 13.The mesh pouch of claim 1, wherein said coating comprises one or moredrugs selected from the group consisting of antimicrobial agents,anesthetics, analgesics, anti-inflammatory agents, anti-scarring agents,anti-fibrotic agents and leukotriene inhibitors.
 14. The mesh pouch ofclaim 13, wherein said drug is an anesthetic.
 15. The mesh pouch ofclaim 14, wherein said anesthetic is bupivacaine HCl.
 16. The mesh pouchof claim 13, wherein said drug is an antimicrobial agent.
 17. The meshpouch of claim 16, wherein said antimicrobial agent is selected from thegroup consisting of rifampin, minocycline, silver/chiorhexidine,vancomycin, a cephalosporin, gentamycin, triclosan and combinationsthereof.
 18. The mesh pouch of claim 16, comprising two antimicrobialagents, said agents being rifampin in combination with gentamycin orvancomycin.
 19. The mesh pouch of claim 16, comprising two antimicrobialagents, said agents being rifampin and a tetracycline derivative. 20.The mesh pouch of claim 19, wherein at least one of said coatingscomprises rifampin and minocycline HCl.
 21. The mesh pouch of claim 13,wherein at least one of said coatings comprises an anti-inflammatoryagent selected from non-selective cox-1 and cox-2 inhibitors.
 22. Themesh pouch of claim 13, wherein at least one of said coatings comprisesan anti-inflammatory agent selected from selective cox-1 or cox-2inhibitors.
 23. The mesh pouch of claim 1, wherein said implantablemedical device is selected from the group consisting of a pacemaker, adefibrillator, a pulse generator, an implantable access system, a drugpump and a neurostimulator.
 24. A mesh pouch having a shape comprising abottom, two sides and a top and a front and a back, and an overall sizeincluding a height of between about 1.5-2.56″, a length of between about1.63-2.4″ and a width of from about 0.24-0.6″ and wherein said front andback surfaces are sealed to each other over at least said bottom andsides for prophylactically encasing and fitting an implantable medicaldevice for implantation in the body, said mesh pouch comprising a poroussurgical mesh which permits tissue ingrowth into said mesh whichstabilizes said implantable medical device within said porous surgicalmesh, and including one or more biodegradable and resorbable syntheticpolymer coatings applied to said porous surgical mesh withoutsubstantially altering the porosity of said porous surgical mesh,whereby the stiffness of said surgical mesh is increased to facilitatesaid implantation, but decreases subsequent to said implantation, saidsynthetic polymer coating including one or more drugs.
 25. The meshpouch of claim 24, wherein said one or more coatings temporarily stiffensaid surgical mesh to at least 1.1 times its original stiffness and saidone or more drugs, alone or in combination, are capable of providingpain relief, inhibiting scarring or fibrosis, and/or inhibitingbacterial growth.
 26. The mesh pouch of claim 24, wherein said surgicalmesh comprises woven polypropylene.
 27. The mesh pouch of claim 24,wherein said one or more biodegradable polymers are selected from thegroup consisting of a polylactic acid, polyglycolic acid,poly(L-lactide), poly(D,L-lactide), polyglycolic acid,poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(glycolide-co-trimethylene carbonate),poly(D,L-lactide-co-caprolactone), poly(glycolide-co-caprolactone),polyethylene oxide, polyoxaester, polydioxanone, polypropylene fumarate,poly(ethyl glutamate-co-glutamic acid),poly(tert-butyloxy-carbonylmethyl glutamate), polycaprolactone,polycaprolactone cobutylacrylate, polyhydroxybutyrate,poly(phosphazene), poly(phosphate ester), poly(amino acid),polydepsipeptide, maleic anhydride copolymer, polyiminocarbonates,poly[(97.5% dimethyltrimethylene carbonate)-co-(2.5% trimethylenecarbonate)], poly(orthoesters), tyrosine-derived polyarylate,tyrosine-derived polycarbonate, tyrosine-derived polyiminocarbonate,tyrosine-derived polyphosphonate, polyalkylene oxide,hydroxypropylmethylcellulose, and copolymers, terpolymers and blends ofany thereof.
 28. A mesh pouch for implantation in the body, said meshpouch having a shape for encasing a medical device and comprising aporous non-resorbable surgical mesh with a coating comprising (1) abiodegradable and resorbable polymer comprising a polyarylate comprisingdesaminotyrosyl-tyrosine (DT)-desaminotyrosyl-tyrosyl ester (DTE)succinate having from about 1% DT to about 30% DT and (2) a drugcomprising an antimicrobial agent comprising rifampin and minocycline,which coating has been applied to said surgical mesh withoutsubstantially altering the porosity of said surgical mesh, whereby thestiffness of said surgical mesh is increased to facilitate saidimplantation, but decreases subsequent to said implantation.
 29. Themesh pouch of claim 28 wherein said polyarylate has about 27.5% DT. 30.A mesh pouch prophylactically encasing at least about 75% of the surfaceof a medical device in said mesh pouch for implantation in the body,said mesh pouch comprising a porous non-resorbable surgical mesh whichis sufficiently porous to permit said medical device to be electricallygrounded to surrounding tissue, said porous surgical mesh including oneor more biodegradable and resorbable synthetic polymer coatings whichhave been applied to said porous surgical mesh without substantiallyaltering the porosity of said surgical mesh, whereby the stiffness ofsaid surgical mesh is increased to facilitate said implantation, butdecreases subsequent to said implantation, wherein at least one of saidbiodegradable polymers comprises one or more tyrosine-derived diphenylmonomer units.
 31. The mesh pouch of claim 30 wherein said polymer is apolyarylate.
 32. The mesh pouch of claim 31 wherein said polyarylate isdesaminotyrosyl-tyrosine (DT)-desaminotyrosyl-tyrosine ethyl ester (DTE)succinate having from about 1% DT to about 30% DT.
 33. The mesh pouch ofclaim 32, wherein said polyarylate is a random copolymer ofdesaminotyrosyl-tyrosine (DT) and an desaminotyrosyl-tyrosyl ester (DTester), wherein said copolymer comprises from about 0.001% DT to about80% DT and said ester moiety can be a branched or unbranched alkyl,alkylaryl, or alkylene ether group having up to 18 carbon atoms, any ofgroup of which can, optionally have a polyalkylene oxide therein.
 34. Amesh pouch for implantation in the body, said mesh pouch having a shapefor encasing a medical device and comprising a porous surgical mesh witha coating comprising (1) a biodegradable and resorbable polymercomprising a polyarylate comprising desaminotyrosyl-tyrosine(DT)-desaminotyrosyl-tyrosyl ester (DTE) succinate having from about 1%DT to about 30% DT and (2) a drug comprising an antimicrobial agent oran anesthetic, which coating has been applied to said surgical meshwithout substantially altering the porosity of said surgical mesh,whereby the stiffness of said surgical mesh is increased to facilitatesaid implantation, but decreases subsequent to said implantation. 35.The mesh pouch of claim 34 wherein said polyarylate has about 27.5% DT.36. The mesh pouch of claim 34 wherein said antimicrobial comprisesrifampin and minocycline.
 37. The mesh pouch of claim 34 wherein saidanesthetic is selected from the group consisting of bupivacaine,lidacaine and mepivacaine.